Match!

Identification of risk loci and a polygenic risk score for lung cancer: a large-scale prospective cohort study in Chinese populations

Published on Oct 1, 2019in The Lancet Respiratory Medicine22.992
· DOI :10.1016/S2213-2600(19)30144-4
Juncheng Dai32
Estimated H-index: 32
(Nanjing Medical University),
Jun Lv17
Estimated H-index: 17
(PKU: Peking University)
+ 43 AuthorsHongbing Shen54
Estimated H-index: 54
(Nanjing Medical University)
Abstract
Summary Background Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. Methods To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. Findings We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10−8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53–2·51; ptrend=2·02 × 10−9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. Interpretation We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. Funding National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.
  • References (39)
  • Citations (1)
📖 Papers frequently viewed together
11 Authors (Huan Li, ..., Daru Lu)
30 Citations
38 Citations
44 Authors (Jacek Marzec, ..., Yong-Jie Lu)
9 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References39
Newest
#1Freddie Ian Bray (IARC: International Agency for Research on Cancer)H-Index: 88
#2Jacques Ferlay (IARC: International Agency for Research on Cancer)H-Index: 66
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 106
view all 6 authors...
3,723 CitationsSource
#1Cheng Wang (Nanjing Medical University)H-Index: 29
#2Rong Yin (Nanjing Medical University)H-Index: 19
Last. Hongbing Shen (Nanjing Medical University)H-Index: 54
view all 26 authors...
Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B ...
5 CitationsSource
#1Ali Torkamani (Scripps Research Institute)H-Index: 38
#2Nathan E. Wineinger (Scripps Research Institute)H-Index: 16
Last. Eric J. Topol (Scripps Research Institute)H-Index: 178
view all 3 authors...
Initial expectations for genome-wide association studies were high, as such studies promised to rapidly transform personalized medicine with individualized disease risk predictions, prevention strategies and treatments. Early findings, however, revealed a more complex genetic architecture than was anticipated for most common diseases — complexity that seemed to limit the immediate utility of these findings. As a result, the practice of utilizing the DNA of an individual to predict disease has be...
113 CitationsSource
#1Douglas E. Wood (UW: University of Washington)H-Index: 43
#2Ella A. Kazerooni (UM: University of Michigan)H-Index: 68
Last. Miranda HughesH-Index: 24
view all 33 authors...
31 CitationsSource
#1Yohan Bossé (Laval University)H-Index: 39
#2Christopher I. Amos (Dartmouth College)H-Index: 101
Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronological presentation of published GWAS on lung cancer susceptibility, survival and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GW...
17 CitationsSource
#1Rui Pan (Nanjing Medical University)H-Index: 1
#2Meng Zhu (Nanjing Medical University)H-Index: 13
Last. Hongbing Shen (Nanjing Medical University)H-Index: 54
view all 12 authors...
The National Central Cancer Registry of China (NCCR) was the only available source of cancer monitoring in China, even though only about 70% of cancer registration sites were qualified by now. In this study, based on a national large prospective cohort-the China Kadoorie Biobank (CKB), we aimed to provide additional cancer statistics and compare the difference of cancer burden between urban and rural areas of China. A total of 497,693 cancer-free participants aged 35–74 years were recruited and ...
19 CitationsSource
#1James D. McKay (IARC: International Agency for Research on Cancer)H-Index: 51
#2Rayjean J. Hung (U of T: University of Toronto)H-Index: 46
Last. Christopher I. Amos (Dartmouth College)H-Index: 101
view all 140 authors...
Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striki...
92 CitationsSource
#1Pradeep Natarajan (Harvard University)H-Index: 24
#2Robin Young (University of Cambridge)H-Index: 22
Last. Sekar Kathiresan (Harvard University)H-Index: 106
view all 14 authors...
Background —Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of two randomized controlled primary prevention trials (ASCOT and JUPITER), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we sought to confirm this observation in a third primary prevention randomized controlled trial. Additionally, we assessed if those at high genetic risk had a greater burden of subc...
92 CitationsSource
#1Rahul S. Desikan (UCSF: University of California, San Francisco)H-Index: 33
#2Chun Chieh Fan (University of California, Berkeley)H-Index: 15
Last. Anders M. Dale (University of California, Berkeley)H-Index: 127
view all 34 authors...
Background Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. Methods and findings Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10−5). We then i...
97 CitationsSource
#1Juncheng Dai (Nanjing Medical University)H-Index: 32
#2Wei Shen (Nanjing Medical University)H-Index: 7
Last. Hong-BingShen (Nanjing Medical University)H-Index: 28
view all 28 authors...
The familial aggregation indicated the inheritance of cancer risk. Recent genome-wide association studies (GWAS) have identified a number of common single nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome-wide complex trait analysis (GCTA) for common cancers at nine anatomical sites...
16 CitationsSource
Cited By1
Newest
#1Yohan Bossé (Laval University)H-Index: 39
#2Simon Martel (Laval University)H-Index: 15
Source